From daemon Mon Feb 1 11:53:50 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id LAA28023; Mon, 1 Feb 1999 11:53:50 -0800 (PST) Message-Id: <199902011953.LAA28023@net.bio.net> To: radoncjc@net.bio.net Date: Mon, 1 Feb 1999 09:38:30 -1000 Reply-To: radoncjc@net.bio.net From: Brian J Goldsmith Subject: February 1999 Internet Radiation Oncology Journal Club (IROJC) February 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 45th collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Perry Grigsby, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology David Larson, M.D. Ph.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology Jim Purdy, Ph.D. Editor, Radiation Oncology Physics and Dosimetry ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. Comments should be in compliance with IROJC commentary rules (see below). In the month that follows this posting of references, submitted comments will be delivered to the e-mail boxes of the IROJC readership, with the goal of stimulating a professional discussion of these references and their subjects. ------------------------------------------------------------ ARCHIVED IROJC POSTINGS and commentary are available on the World Wide Web! Look for them on http://www.bio.net/ Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then go to "RADIATION-ONCOLOGY/Prototype". Or directly access the RADIATION-ONCOLOGY folder at http://www.bio.net/hypermail/RADIATION-ONCOLOGY/ There's also a freeWAIS search tool at the website, for searching archived postings for keywords or phrases! ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 2/99. (2) Address the readership at large - not the Editor who suggested the reference. The Editor is under no obligation to respond to questions posed by the IROJC readership. (3) The Editor's selection is not necessarily an endorsement of the authors' conclusions. In fact, articles may be selected for criticism. (4) Comments posted to the Internet are public. Professional wording is prudent. (5) Comment only on journal articles that you have read recently, and please keep comments specific. (6) In order to minimize confusion, limit comments to the current month's list of references. Example: comments submitted in February about a January IROJC reference will not be posted. (7) Please sign all comments and questions to the IROJC. By identifying yourself, you promote a more collegial and friendly environment! (8) Address to the Moderator (bjg@mhpcc.edu) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 2/99 AU: Craft A, Cotterill S, Malcolm A, Spooner D, Grimer R, Souhami R, Imeson J, Lewis I. TI: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. SO: J Clin Oncol 1998 Nov;16(11):3628-33. URL: http://www.jco.org/abs16_11/v16n11p3628.html Abstract: PURPOSE: To investigate the possibility that the substitution of ifosfamide for cyclophosphamide therapy for Ewing's sarcoma will improve survival over that seen in the first United Kingdom Children's Cancer Study Group (UKCCSG) Ewing's tumor study (ET-1). PATIENTS AND METHODS: Between 1987 and 1993,243 patients (138 men or boys) were entered onto the study. The median age was 13.5 years (range, 1.5 to 27 years). The median follow-up was 58 months. Chemotherapy included four courses of vincristine 2 mg/m2; ifosfamide 9 g/m2; and doxorubicin 60 mg/m2 administered every 3 weeks. Treatment of the primary tumor was with surgery and/or radiotherapy followed by ifosfamide 6 g/m2; doxorubicin 60 mg/m2; and vincristine 2 mg/m2; with actinomycin D 1.5 mg/m2 substituted for doxorubicin after a total dose of 420 mg/m2. RESULTS: Two hundred one patients had no metastases. One hundred eighteen patients had tumors of the axial skeleton and 125 patients had limb primary tumors. The major toxicities were hematologic and infective, but there were no toxic deaths. The overall survival rate was 62% (95% confidence interval [CI], 56 to 69) and relapse-free survival (RFS) 56% (95% CI, 49 to 62). For those with no metastases at diagnosis, the RFS rate was 62% and for those with metastases, 23%. Multivariate analysis showed age and site to have a significant effect on RFS. Pelvic sites had the worst RFS rate of 41%; other axial sites, 55%; and extremity tumors, 73%. Age younger than 10 years had an RFS rate of 86% versus 55% for older patients. The local relapse rate for axial tumors was 20% and for limb primary tumors was 2.4%. CONCLUSION: The 5-year survival rate of 62% is improved compared with the 44% survival rate achieved in ET-1. This is probably caused by the use of higher doses of ifosfamide compared with relatively low doses of cyclophosphamide in ET-1. Editor's comments: Although the point of this paper is the advantage of adding Ifosfamide to the chemotherapy program in Ewing's Sarcoma, there are interesting points to be learned about local control. The protocol guidelines recommended surgical excision in all cases, reflecting the current bias against radiotherapy in Ewing's Sarcoma. However, the local failure rate was, in my opinion, unacceptable high. The data are presented as local control by site and local therapy, thus separating the favorable "other sites" from the axial sites, where the local relapse rate was 20.5%. With radiotherapy alone there were 18% local relapses, while with resection alone there were 29% local relapses! The numbers of patients with surgery and RT are too small to be useful. The authors correctly state that they cannot draw firm conclusions about the role of surgery, because its use was determined by the site of the primary. Comparisons with "p" values are not useful because treatment was not randomized and because of the factors which influence therapy decisions. However, one point can be made for certain and that is that surgical resection and chemotherapy, without radiotherapy is disappointing with respect to local control for Ewing's sarcoma arising in an axial site. ****************** Head/Neck/Skin: Foote 2/99 AU: Chua DT, Sham JS, Choy D, Lorvidhaya V, Sumitsawan Y, Thongprasert S, Vootiprux V, Cheirsilpa A, Azhar T, Reksodiputro AH. TI: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group. SO: Cancer 1998 Dec 1;83(11):2270-83. Abstract: BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size greater than or equal to 3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P equals 0.45; 3-year OS rate: 78% vs. 71%, P equals 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P equals 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P equals 0.21). In the subgroup of 49 patients with bulky neck lymph nodes greater than 6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P equals 0.026) and OS (3-year OS rate: 73% vs. 37%, P equals 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials. Editor's comments: See the accompanying editorial by Wong, Is Chemotherapy Beneficial in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma? Cancer 83:2255-58, 1998. ****************** GYN: Grigsby 2/99 No Reference Selected ****************** GI / Soft Tissue Sarcoma: Tepper 2/99 No Reference Selected ****************** CNS: Larson 2/99 No Reference Selected ****************** Physics/Dosimetry: Purdy 2/99 AU: Khoo VS, Bedford JL, Webb S, Dearnaley DP. TI: Comparison of 2D and 3D algorithms for adding a margin to the gross tumor volume in the conformal radiotherapy planning of prostate cancer. SO: Int J Radiat Oncol Biol Phys 1998 Oct 1;42(3):673-9. Abstract: PURPOSE: To evaluate the adequacy of tumor volume coverage using a three-dimensional (3D) margin-growing algorithm compared to a two-dimensional (2D) margin-growing algorithm in the conformal radiotherapy planning of prostate cancer. METHODS AND MATERIALS: Two gross tumor volumes (GTV) were segmented in each of 10 patients with localized prostate cancer; prostate gland only (PO) and prostate with seminal vesicles (PSV). A predetermined margin of 10 mm was applied to these two groups (PO and PSV) using both 2D and 3D margin-growing algorithms. The 2D algorithm added a transaxial margin to each GTV slice, whereas the 3D algorithm added a volumetric margin all around the GTV. The true planning target volume (PTV) was defined as the region delineated by the 3D algorithm. The adequacy of geometric coverage of the GTV by the two algorithms was examined in a series of transaxial planes throughout the target volume. RESULTS: The 2D margin-growing algorithm underestimated the PTV by 17% (range 12-20) in the PO group and by 20% (range 13-28) for the PSV group when compared to the 3D-margin algorithm. For the PO group, the mean transaxial difference between the 2D and 3D algorithm was 3.8 mm inferiorly (range 0-20), 1.8 mm centrally (range 0-9), and 4.4 mm superiorly (range 0-22). Considering all of these regions, the mean discrepancy anteriorly was 5.1 mm (range 0-22), posteriorly 2.2 (range 0-20), right border 2.8 mm (range 0-14), and left border 3.1 mm (range 0-12). For the PSV group, the mean discrepancy in the inferior region was 3.8 mm (range 0-20), central region of the prostate was 1.8 mm (range 0-9), the junction region of the prostate and the seminal vesicles was 5.5 mm (range 0-30), and the superior region of the seminal vesicles was 4.2 mm (range 0-55). When the different borders were considered in the PSV group, the mean discrepancies for the anterior, posterior, right, and left borders were 6.4 mm (range 0-55), 2.5 mm (range 0-20), 2.6 mm (range 0-14), and 3.9 mm (range 0-45), respectively. Underestimation of the required margin with the 2D algorithm occurred when the transaxial definition of the GTV shifted in position significantly between successive adjacent slices, resulting in transaxial discrepancies of up to 22 mm and 55 mm, respectively, for the PO and PSV groups. In the superior regions, the 2D algorithm was inadequate, often providing a margin of less than 3 mm compared to the 10 mm margin delineated by the 3D algorithm. CONCLUSION: This study illustrates that target margins added by a laminar method in the transaxial plane are inadequate for covering a 3D tumor volume so that a margin-growing algorithm which fully takes into account the 3D shape of the GTV should be used. If a 2D-margin method is utilized, an appreciation of spatial margins in 3D is required. ****************** Breast: Recht 2/99 AU: Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. TI: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. SO: J Clin Oncol 1998 Aug;16(8):2625-31. URL: http://www.jco.org/abs16_8/v16n8p2625.html Abstract: PURPOSE: To compare the risk for fatal myocardial infarction (MI) after adjuvant radiotherapy (RT) for left-sided breast cancer with the risk for MI after adjuvant RT for right-sided breast cancer. METHODS: We studied women with local- and regional-stage breast cancer diagnosed from 1973 to 1992 from the Surveillance, Epidemiology, and End-Results (SEER) cancer registries. We performed life-table analysis, the log-rank test, and Cox proportional hazards regression to compare the time to fatal MI from diagnosis between left-sided and right-sided cases, censoring deaths from other causes. RESULTS: Among irradiated patients, the relative risk (RR) for fatal MI in women with left-sided breast cancer was 1.17 (95% confidence interval [CI], 1.01 to 1.36), controlling for age, compared with those with right-sided breast cancer. The RR for fatal MI among left-sided cases was increased for those under the age of 60 years (RR equals 1.98; 95% CI, 1.31 to 2.97) compared with right-sided cases, but not at age 60 years or older. Among women with irradiated regional-stage cancer who were younger than 60 years of age, the risk was significantly increased (RR equals 2.24; 95% CI, 1.38 to 3.64) for those with left-sided compared withright-sided breast cancer, but not among patients aged 60 years or older. Among irradiated local-stage cases, the risk for those with left-sided breast cancer was not significantly elevated in either age category. Analysis of 5-year conditional survival cohorts showed an increased risk for irradiated left-sided cases among women younger than 60 years of age in the 10- to 15-year conditional survival cohort (RR equals 5.28; 95% CI, 1.82 to 15.3). CONCLUSION: Adjuvant RT for left-sided breast cancer diagnosed in women younger than 60 years of age is associated with a higher risk for fatal MI 10 to 15 years later compared with adjuvant RT for right-sided cases. Editor's comments: This important article shows that the use of radiotherapy techniques employed in the patients in this data-base increased the risk of fatal myocardial infarction in women younger than age 60. It is puzzling why older women were not also affected, as previous studies have shown (see the authors' discussion for references). However, a broader issue is whether these results apply to patients irradiated today. There are two aspects to this question. First, the effects of different treatment techniques used in the SEER population could not be analyzed, as such information was not available. The majority of patients treated with breast-conserving therapy (BCT) today have negative axillary nodes; hence, only the breast is routinely irradiated, without any specific attempt to treat the internal mammary nodes (IMNs) (with the exception of centers that routinely do such treatment for patients with central or medial lesion). The Karolinska Hospital group in Stockholm found no evidence of increased rates of myocardial infarction in patients treated to the breast only with tangential fields, with a median follow-up of 9 years, as compared to patients treated with mastectomy or between patients with right- and left-sided lesions.[1] It is likely that most patients in the SEER data-base were treated with techniques that attempted to include the IMNs. Even in this setting, it is not clear how representative their results are. In the Stockholm randomized study of pre- or postmastectomy RT versus observation, treatment technique clearly impacted the risk of cardiac events.[2] Patients who received RT to one internal-mammary chain using techniques that exposed a "low" or "intermediate" dose-volume of the heart did not experience an increased risk of cardiac mortality; whereas patients treated to a "high" dose-volume had an increased risk. These findings persist in a recently-published update of their experience with a median follow-up of 20 years.[3] Similarly, there was no difference in the incidence of cardiac events in the JCRT breast-conservation series between patients with right- and left-sided lesions who had a potential follow-up time of at least 12 years, despite the fact that (during this period) the IMNs were commonly in deep tangent fields.[4] Second (and potentially countering the good news from these other studies), patients who might receive IMN RT today are also likely to receive potentially cardiotoxic drugs. We have very little data as yet regarding the long-term effects of combining such drugs with RT. In a protocol conducted at the Dana-Farber Cancer Institute, there was no evidence of increased cardiac toxicity in patients receiving a moderate total dose of doxorubicin (225 mg/square meter in 5 doses) even when IMN RT was given to a hockey-stick photon field or with deep left-sided tangents.[5] However, patients receiving higher doses (450 mg/square meter in 10 treatments) plus such irradiation had a significantly increased risk. (See the discussion in this article for a summary of other information on this subject.) However, the number of patients in this study was small, and the length of follow-up was relatively short. Also, no one knows whether adding taxanes or Herceptin to anthracyclines plus RT might increase such cardiac risks. Thus, the ultimate cardiac morbidity and mortality due to RT for patients with breast cancer, particularly when specific IMN treatment is given, remains an open question. 1. Rutqvist LE, Liedberg A, Hammar N, et al: Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation. Int J Radiat Oncol Biol Phys 40:359-363, 1998 2. Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992 3. Gyenes G, Rutqvist LE, Liedberg A, et al: Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol 48:185-190, 1998 4. Nixon AJ, Manola J, Gelman R, et al: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998 5. Shapiro CL, Harrigan-Hardenbergh P, Gelman R, et al: Cardiac effects of adjuvant doxorubicin and radiation therapy in node positive breast cancer patients. J Clin Oncol 16:3493-3501, 1998 ****************** RES: Hoppe 2/99 AU: Wirth A, Chao M, Corry J, Laidlaw C, Yuen K, Ryan G, Byram D, Davis S, Kiffer J, Quong G, and Liew K. TI: Mantle irradiation alone for clinical stage I-II Hodgkin's disease: long-term follow-up and analysis of prognostic factors in 261 patients. SO: J Clin Oncol 17:230-240. URL: http://www.jco.org/abs17_1/v17n1p230.html Abstract: PURPOSE: To evaluate mantle radiotherapy (MRT) alone as the initial therapy of patients with clinical stage (CS) I-II Hodgkin's disease (HD). PATIENTS AND METHODS: We performed a retrospective study of patients treated with MRT alone for CS I-II supradiaphragmatic HD between 1969 and 1994. Prognostic factor analysis was performed for progression-free survival (PFS) and overall survival (OS). Outcome was also assessed in favorable cohorts defined in the literature. RESULTS: There were 261 eligible patients. The median follow-up period for surviving patients was 8.4 years (range, 1.8 to 27.4 years). The 10-year OS rate was 73%. Multifactor analysis for OS showed that age was the only important prognostic factor. The 10-year PFS rate was 58%. On multifactor analysis for PFS, the most important prognostic factors were clinical stage, B symptoms, histology, number of sites, and tumor bulk. The 10-year PFS rate for lymphocyte-predominant disease was 81% for stage I and 78% for stage II. In favorable patient cohorts defined in the literature, the 10-year PFS rate ranged from 70% to 73% for the whole group and from 71% to 90% in patients with favorable stage I disease, but only from 48% to 57% in patients with favorable stage II disease. On competing-risks analysis, the cumulative 10-year incidence of first site of failure in the para-aortic/splenic region alone was 10.5%. Sixty percent of relapsed patients remain progression-free at 10 years after chemotherapy salvage. CONCLUSION: These results support the use of MRT alone in patients with favorable CS I HD and CS I-II HD with lymphocyte-predominant histology. The remainder of patients with CS I-II HD require more intensive treatment. Editor's comments: This is a thorough, well-written and well-referenced report analyzing the Australian experience using mantle alone for CS I-II HD (no laparotomy). The long term outcome is excellent for selected favorable subsets of patients. The essential question is, why are these results (in the favorable subsets) superior to those of the EORTC in the H7VF trial? In the H7VF trial, patient eligibility criteria included: CSIA, female, younger than 40 years, LP or NS histology, and no bulky mediastinal adenopathy. Following treatment with mantle irradiation alone, the freedom from treatment failure has dropped below 70%, and the EORTC has abandoned this trial. Wirth et al. report 90% of patients with very favourable or favourable Stage I disease to be progression-free (Fig. 4) and suggest that this group is suitable for treatment with mantle alone. It is possible that the answer lies in the distribution of histologies. Lymphocyte predominance Hodgkin's disease may account for the majority of the favourable and very favourable Stage I patients in this series. The numbers are not provided directly, but there were 56 LP patients and 9 of them were noted to be CS II. It is not unreasonable to suspect that the majority of the 56 Stage I LP patients made up the group of 62 patients with favourable or very favourable disease characteristics. Likewise, there has not been a report breaking down the histologies in the H7VF trial, but these numbers would be very helpful to have, especially considering all the things that seem to be different about LP. LPHD marks as a B-cell lymphoma, often presents with limited peripheral disease (high neck or inguinal-femoral), can be treated with limited radiation fields, and more commonly is associated with late relapse than other histologies. Treatment with less than a mantle is often sufficient, for example in high neck presentations it is not necessary to treat the mediastinum, thereby avoiding significant toxicity. It would be interesting to know if these patients (and those rare few with limited intrathoracic NS) account for the excellent outcome of the very favourable and favourable groups in this study. ****************** Lung/Mediastinum: Turrisi 2/99 AU: Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, Garcia M, Lianes P, Montalar J, Vadell C, Gonzalez-Larriba JL, Nguyen B, Artal A, Rosell R. TI: Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. SO: J Clin Oncol 1999; 17:12-17. URL: http://www.jco.org/abs17_1/v17n1p12.html Abstract: PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P equals .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P equals .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P equals .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC. Editor's comments: The role of systemic therapy in NSCLC continues to emerge. Chemotherapy is here to stay, and the relative merits of the newer agents: gemcitabine, taxanes (docetaxel & paclitaxel), tirapazamine, topoisomerase-1 inhibitors (topotecan and irinotecan), and vinorelebine, either alone or in combination with a platinoid occupy many pages. The highlighted article is from Spain, where gemcitabine enjoys remarkable market share and popularity similar to the heavy use of paclitaxel in the USA. Last month's JCO (1998) 16: 3524-3527 provided an article by Treat and colleagues on the least heralded new drug - tirapazamine. Contrary to an off the cuff remark I heard by one radiation oncology colleague, these drugs are not a flash in the pan, but are here to stay. The current trend is to study these drugs in "advanced disease" -- which means stage IV to all, and some stage III. Some stage III patients are not destined to do well with radiation oncology intervention - - clearly those with pleural effusion fit this category, possibly others with very large, bulky primaries or bulky and expansive regional nodes. However, the use of thoracic radiotherapy seems important to survival for most patients with stage III-a and III-b (see Kubota - 1994 JCO 12: 1547). Our mission is to clearly establish what methods are best to incorporate these new drugs with radiotherapy. DO NOT ASSUME that they will all behave the same, can be used interchangeably with older regimens, that sequential use is safe only concurrent poses risks. Is there a best regimen? Clearly no. In fact, it is hard to prove that the new combinations, despite millions spent on marketing, are better than the old stand-by, platinum-etoposide. Some of the aging lions of medical oncology gag at the choice of platinum-etoposide as a standard because etoposide has a relatively poor response rate as a single agent against NSCLC. This months selection highlights that response rates are not always surrogates for survival. The dominant Taxol used in the US seemed the best thing since sliced bread. The initial ECOG trial suggested a survival advantage, but 3 of 4 Taxol trials reported at ASCO this year could not support a survival advantage. The original trial used 24 hr. infusions, the current trend is for 3-hr infusions or even shorter. At the end of the day, the response rates are better, but the survival may not be. One trial even suggests that the survival is better when platinum etoposide is followed by carboplatinum-paclitaxel. All of the new drugs have activity in NSCLC. Today I have to say that we do not know which drugs are best, the necessity of more than one drug (not to mention a third!), or for that matter what drugs are standard. Some leaders have injudiciously suggested that if your treatment team suggests an older combination, you should seek another opinion from someone that uses, and then names a product from a pharmaceutical house that has sponsored many conferences and supplied other means of support for the expert. Caveat emptor! (Let the buyer beware). Our mission will be to work at finding the best drugs and the best ways to combine chemotherapeutics with radiotherapy. Gene therapy, anti-angiogenesis agents, and other new ideas will surface, but our job is clear in today's management of patients. ****************** GU: Roach 2/99 No Reference Selected ****************** Radiobiology: Withers 2/99 AU: Pollack A, Zagars GK. TI: External beam radiotherapy dose response of prostate cancer. SO: Int J Radiat Oncol Biol Phys 1997 Dec 1;39(5):1011-8. Abstract: PURPOSE: To determine the external beam radiotherapy dose response of palpable Stage T1-T4, mostly Nx, patients with adenocarcinoma of the prostate. METHODS AND MATERIALS: There were 938 men consecutively treated between 1987 and 1995 who had pretreatment prostate specific antigen (PSA) levels. Posttreatment failure was defined as disease recurrence and/or two elevations in PSA on consecutive follow-up visits. The radiotherapy technique consisted of a four-field box with a small four-field reduction after 46 Gy in 844 patients (total dose of 60-70 Gy) or with a six-field conformal boost after 46 Gy in 94 patients (total dose of 74-78 Gy). Neoadjuvant or adjuvant androgen ablation was not used in any patient. Median follow-up was 40 months. RESULTS: The mean and median radiotherapy doses for the entire group were 67.8 +/- 13.3 Gy (+/-SEM) and 66 Gy. The mean radiotherapy dose was higher in those who had Stage T3/T4 disease, Gleason scores of 8-10, or pretreatment PSAs of greater than 4 ng/ml. In general, patients with more aggressive pretreatment prognostic features were treated to higher doses; yet, those that relapsed or had a rising PSA were treated to significantly lower doses. Actuarial analyses were facilitated by dividing patients into three dose groups: less than or equal to 67, greater than 67 to 77, and greater than 77 Gy. The actuarial freedom from failure rates at 3 years were 61, 74, and 96% for the low, intermediate, and high dose groups. Stratification of the patients by pretreatment PSA revealed that dose was a significant correlate of freedom from relapse or a rising PSA for those with PSAs greater than 4 to 10, greater than 10 to 20, and greater than 20 ng/ml. The only patients in which an improvement in outcome was not related to higher doses were those with a pretreatment PSA less than or equal to 4 ng/ml. Dose was significantly associated with freedom from failure for Stage T1/T2 and Stage T3/T4 patients, as well as for those stratified by Gleason score. Multivariate analysis using Cox proportional hazards models showed that dose was an independent and highly significant predictor of relapse or a rising PSA. CONCLUSION: This retrospective review strongly indicates that radiotherapy dose to the prostate is critical to the cure of prostate cancer, even for favorable patients with pretreatment PSAs of greater than 4 to10 ng/ml, Stages T1/T2, or Gleason scores of 2-6. Final confirmation awaits the results of our randomized trial. Editor's comments: This is an important paper validating the escalation of dose to prostate cancer using conformal techniques. The clinical implications of this large study are great, but, at the same time, the results provide some titillating material for speculation in biology and radiobiology. The increase in rate of freedom from PSA failure (between 50% and 80%) was about 4% per Gy. This steep dose response corresponds to effective D0 and D10 values of about 7 Gy and 16 Gy respectively. (D10 is the dose which would reduce survival by one decade). Most analyses of human tumor responses are less steep than that shown in Fig. 2 of this paper. Since there was considerable variability in initial tumor volume, PSA level and Gleason score, the steep slope suggests that other causes of heterogeneity in responses may not be as great as in some other tumor sites such as head and neck. The treatment parameters were tightly controlled and, with this relatively indolent type of cancer, one would expect less heterogeneity in tumor clonogen regrowth rates during therapy. But maybe there is also less variation in inherent radiosensitivity. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC